What is Clonazepam?

Introduction

Clonazepam, sold under the brand name Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, anxiety, and the movement disorder known as akathisia. It is a tranquiliser of the benzodiazepine class. It is typically taken by mouth. Effects begin within one hour and last between six and twelve hours.

Common side effects include sleepiness, poor coordination, and agitation. Long-term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. Dependence occurs in one-third of people who take clonazepam for longer than four weeks. There is an increased risk of suicide, particularly in people who are already depressed. If used during pregnancy it may result in harm to the foetus. Clonazepam binds to GABAA receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (GABA).

Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche. It is available as a generic medication. In 2019, it was the 46th most commonly prescribed medication in the United States, with more than 15 million prescriptions. In many areas of the world it is commonly used as a recreational drug.

Medical Uses

Clonazepam is prescribed for short term management of epilepsy, anxiety, and panic disorder with or without agoraphobia.

Seizures

Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.

Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam. As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.

It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.

Anxiety Disorders

  • Panic disorder with or without agoraphobia.
  • Clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use.

The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo-controlled. Clonazepam is also effective in the management of acute mania.

Muscle Disorders

Restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short-term. Rapid eye movement sleep behaviour disorder responds well to low doses of clonazepam.

  • The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.
  • Spasticity related to amyotrophic lateral sclerosis.
  • Alcohol withdrawal syndrome

Other

  • Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol, or risperidone. The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.
  • Hyperekplexia: A very rare neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia.
  • Many forms of parasomnia and other sleep disorders are treated with clonazepam..
  • It is not effective for preventing migraines.

Contraindications

  • Coma.
  • Current alcohol use disorder.
  • Current substance use disorder.
  • Respiratory depression.

Adverse Effects

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Common

  • Sedation.
  • Motor impairment.

Less Common

  • Confusion.
  • Irritability and aggression.
  • Psychomotor agitation.
  • Lack of motivation.
  • Loss of libido.
  • Impaired motor function.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness.
  • Cognitive impairments.
  • Hallucinations.
  • Short-term memory loss.
  • Anterograde amnesia (common with higher doses).
  • Some users report hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep.
    • This is likely the result of the medication’s long half-life, which continues to affect the user after waking up.
    • While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.
    • After regular use, rebound insomnia may occur when discontinuing clonazepam.
  • Benzodiazepines may cause or worsen depression.

Occasional

  • Dysphoria.
  • Induction of seizures or increased frequency of seizures.
  • Personality changes.
  • Behavioural disturbances.
  • Ataxia.

Rare

  • Cognitive Euphoria.
  • Suicide through disinhibition.
  • Psychosis.
  • Incontinence.
  • Liver damage.
  • Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities).
  • Rage.
  • Excitement.
  • Impulsivity.
  • The long-term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.

Drowsiness

Clonazepam, like other benzodiazepines, may impair a person’s ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.

Withdrawal-Related

  • Anxiety.
  • Irritability.
  • Insomnia.
  • Tremors.
  • Headaches.
  • Stomach pain.
  • Hallucinations.
  • Suicidal thoughts or urges.
  • Depression.
  • Fatigue.
  • Dizziness.
  • Sweating.
  • Confusion.
  • Potential to exacerbate existing panic disorder upon discontinuation.
  • Seizures similar to delirium tremens (with long-term use of excessive doses).

Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behaviour. Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal. Use of alcohol or other central nervous system (CNS)-depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug.

A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.

Tolerance and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator. One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitisation, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.

Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.

Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life-threatening condition, status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects. Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.

Overdose

Refer to Benzodiazepine Overdose.

Excess doses may result in:

  • Difficulty staying awake.
  • Mental confusion.
  • Impaired motor functions.
  • Impaired reflexes.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness.
  • Respiratory depression.
  • Low blood pressure.
  • Coma.

Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam. The combination of clonazepam and certain barbiturates (for example, amobarbital), at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression.

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.

Detection in Biological Fluids

Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or whole blood in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analysed quickly to minimise losses.

Special Precautions

The elderly metabolise benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.

The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.

Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.

Doses higher than 0.5-1 mg per day are associated with significant sedation.

Clonazepam may aggravate hepatic porphyria.

Clonazepam is not recommended for patients with chronic schizophrenia. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behaviour in individuals with chronic schizophrenia.

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.

Interactions

Clonazepam decreases the levels of carbamazepine, and, likewise, clonazepam’s level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin (diphenylhydantoin). In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%. Clonazepam increases the levels of primidone and phenobarbital.

Combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects.

Pregnancy

There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing foetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the foetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors, or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnoea, risk of aspiration of feeds, diarrhoea and vomiting, and growth retardation. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in newborns. If clonazepam is used during pregnancy or breastfeeding, it is recommended that serum levels of clonazepam are monitored and that signs of central nervous system depression and apnoea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.

Pharmacology

Mechanism of Action

Clonazepam enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects. It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.

Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.

Clonazepam’s primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAA receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA’s inhibitory effects and resultant central nervous system depression. In addition, clonazepam decreases the utilisation of 5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of “highly potent” benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in the feline brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarisation-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.

Clonazepam is a 2′-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.

Pharmacokinetics

Clonazepam is lipid-soluble, rapidly crosses the blood-brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine. Clonazepam is metabolised extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19-60 hours. Peak blood concentrations of 6.5-13.5 ng/mL were usually reached within 1-2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4-8 hours.

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.

Clonazepam has plasma protein binding of 85%. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. These metabolites are excreted by the kidney.

It is effective for 6-8 hours in children, and 6-12 in adults.

Society and Culture

Recreational Use

Refer to Benzodiazepine Misuse.

A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.

Formulations

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.

Brand Names

It is marketed under the trade name Rivotril by Roche in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia,[136] Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Pakistan, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the trade name Klonopin by Roche in the United States. Other names, such as Clonoten, Ravotril, Rivotril, Iktorivil, Clonex (Israel), Paxam, Petril, Naze, Zilepam and Kriadex, are known throughout the world.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Clonazepam >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Butriptyline?

Introduction

Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an “atypical” or “second-generation” TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.

Brief History

Butriptyline was developed by Wyeth, an American pharmaceutical company, and introduced in the United Kingdom in either 1974 or 1975.

Medical Uses

Butriptyline was used in the treatment of depression. It was usually used at dosages of 150-300 mg/day.

Side Effects

Butriptyline is closely related to amitriptyline, and produces similar effects as other TCAs, but its side effects like sedation are said to be reduced in severity and it has a lower risk of interactions with other medications.

Butriptyline has potent antihistamine effects, resulting in sedation and somnolence. It also has potent anticholinergic effects, resulting in side effects like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. The drug has relatively weak effects as an alpha-1 blocker and has no effects as a norepinephrine reuptake inhibitor, so is associated with little to no antiadrenergic and adrenergic side effects.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Pharmacology

Pharmacodynamics

In vitro, butriptyline is a strong antihistamine and anticholinergic, moderate 5-HT2 and α1-adrenergic receptor antagonist, and very weak or negligible monoamine reuptake inhibitor. These actions appear to confer a profile similar to that of iprindole and trimipramine with serotonin-blocking effects as the apparent predominant mediator of mood-lifting efficacy.

However, in small clinical trials, using similar doses, butriptyline was found to be similarly effective to amitriptyline and imipramine as an antidepressant, despite the fact that both of these TCAs are far stronger as both 5-HT2 antagonists and serotonin–norepinephrine reuptake inhibitors. As a result, it may be that butriptyline has a different mechanism of action, or perhaps functions as a prodrug in the body to a metabolite with different pharmacodynamics.

Pharmacokinetics

Therapeutic concentrations of butriptyline are in the range of 60-280 ng/mL (204-954 nmol/L). Its plasma protein binding is greater than 90%.

Chemistry

Butriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline, nortriptyline, and protriptyline. Butriptyline is an analogue of amitriptyline with an isobutyl side chain instead of a propylidene side chain. It is a tertiary amine TCA, with its side chain-demethylated metabolite norbutriptyline being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of butriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C21H27N with a molecular weight of 293.446 g/mol. The drug has been used commercially both as the free base and as the hydrochloride salt. The CAS Registry Number of the free base is 15686-37-0 and of the hydrochloride is 5585-73-9.

Society and Culture

Generic Names

Butriptyline is the English and French generic name of the drug and its International Non-Propriety Name (INN), British Approved Name (BAN), and Denomination Commune Francaise (DCF), while butriptyline hydrochloride is its BANM and (United States Adopted Name (USAN). Its generic name in Latin is butriptylinum, in German is butriptylin, and in Spanish is butriptylina.

Brand Names

Butriptyline has been marketed under the brand names Evadene, Evadyne, Evasidol, and Centrolese.

Availability

Butriptyline has been marketed in Europe, including in the United Kingdom, Belgium, Luxembourg, Austria, and Italy.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Butriptyline >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Bromazolam?

Introduction

Bromazolam (XLI-268) is a triazolobenzodiazepine (TBZD) which was first synthesised in 1976, but was never marketed. It has subsequently been sold as a designer drug, first being definitively identified by the EMCDDA in Sweden in 2016.

Outline

It is the bromo instead of chloro analogue of alprazolam and has similar sedative and anxiolytic effects to it and other benzodiazepines. Bromazolam is a non subtype selective agonist at the benzodiazepine site of GABAA receptors, with a binding affinity of 2.81nM at the α1 subtype, 0.69nM at α2 and 0.62nM at α5.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Bromazolam >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Aripiprazole?

Introduction

Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressive disorder (MDD), tic disorders and irritability associated with autism. It is taken by mouth or injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.

Common side effects include vomiting, constipation, sleepiness, dizziness, weight gain and movement disorders. Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia and anaphylaxis. It is not recommended for older people with dementia-related psychosis due to an increased risk of death. In pregnancy, there is evidence of possible harm to the baby. It is not recommended in women who are breastfeeding. It has not been very well studied in people less than 18 years old. The exact mode of action is not entirely clear but may involve effects on dopamine and serotonin.

Aripiprazole was approved for medical use in the United States in 2002. It is available as a generic medication. In 2019, it was the 101st most commonly prescribed medication in the United States, with more than 6 million prescriptions. Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical.

Brief History

Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.

It was approved by the US Food and Drug Administration (FDA) for schizophrenia in November 2002, and the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 01 October 2004; as an adjunct for major depressive disorder on 20 November 2007; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.

Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.

In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS’s off-label marketing of aripiprazole for children and older people with dementia.

In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.

As of 2013, Abilify had annual sales of US$7 billion. In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.

Otsuka’s US patent on aripiprazole expired on 20 October 2014, but due to a paediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the US District Court in New Jersey.

Otsuka’s European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014. The UK Intellectual Property Office decided on 04 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.

From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.

In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.

In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.

In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.

Medical Uses

Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.

Schizophrenia

The 2016 NICE guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second line treatment after risperidone for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia. A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second generation antipsychotics for people who have trouble taking medication as directed or who prefer it.

A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor. A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behaviour, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse. A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia. Accordingly, part of its methodology on quality of evidence is based on quantity of qualified studies.

A 2013 review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.

In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.

The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic, and that such treatment should continue for at least 1-2 years, as “There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period”. The guideline further notes that “Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)”.

The British Association for Psychopharmacology and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person’s preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics

Bipolar Disorder

Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents. Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression. Thus, it is often used in combination with an additional mood stabiliser; however, co-administration with a mood stabiliser increases the risk of extrapyramidal side effects.

Major Depression

Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning. Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram, and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.

Autism

Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours. Adverse effects include weight gain, sleepiness, drooling and tremors. It is suggested that children and adolescents need to be monitored regularly while taking this medication, to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long term use.

Tic Disorders

Aripiprazole is approved for the treatment of Tourette’s syndrome. It is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses

Obsessive-Compulsive Disorder

A 2014 systematic review and meta-analysis concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with selective serotonin reuptake inhibitors (SSRIs) alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms. Risperidone, another second-generation antipsychotic, appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines. However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD. Aripiprazole is not currently approved for the treatment of OCD and is instead used off-label for this indication.

Adverse Effects

In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.

Uncontrolled movement such as restlessness, tremors, and muscle stiffness may occur.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose

Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3-4 fold over normal therapeutic levels; as of 2008 no deaths had been recorded.

Interactions

Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.

Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.

Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid attention-deficit hyperactivity disorder (ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.

Pharmacology

Pharmacodynamics

Aripiprazole’s mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D2). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors, D3, and partially D4 and is a partial activator of serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7). It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.

As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D2 partial agonist (with an intrinsic activity of ~25%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, in vitro, to bind to and/or induce receptor conformations (i.e. facilitate receptor shapes) in such a way as to not only prevent receptor internalisation (and, thus, lower receptor density) but even to lower the rate of receptor internalisation below that of neurons not in the presence of agonists (including dopamine) or antagonists. It is often the nature of partial agonists, including aripiprazole, to display a stabilising effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole’s partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D2 receptor occupancy (approximately 32%, 53%, 72%, 80%, and 97% at daily dosages of 0.5 mg, 1 mg, 2 mg, 10 mg, and 40 mg respectively) as well as balanced selectivity for pre- and postsynaptic receptors (as suggested by its equal affinity for both D2S and D2L receptor forms). Aripiprazole has been characterised as possessing predominantly antagonistic activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors; however, while this explanation intuitively explains the drug’s efficacy as an antipsychotic, as degree of agonism is a function of more than a drug’s inherent properties as well as in vitro demonstration of aripiprazole’s partial agonism in cells expressing postsynaptic (D2L) receptors, it was noted that “It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D2 receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5-1 pmol/mg). Instead, the current data are most parsimoniously explained by the ‘functional selectivity’ hypothesis of Lawler et al (1999)”. Aripiprazole is also a partial agonist of the D3 receptor. In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.

Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%). Casting doubt on the significance of aripiprazole’s agonism of 5-HT1A receptors, a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT1A receptor occupancy to be only 16% compared to ~90% for D2. It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%), and like other atypical antipsychotics, displays a functional antagonist profile at this receptor. The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor. At the 5-HT2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, “Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC50 of 11 nM”. Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity; this property may underlie the minimal weight gain seen in the course of therapy. At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.

Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions. The ‘functional-selectivity’ hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially ‘sensed’ by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.

Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an anti-obsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as anti-obsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favourable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have anti-obsessional and anorectic actions in humans.

Wood and Reavill’s (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor. It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.

Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduce.

Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3-5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via faeces and urine.

Chemistry

Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs.

Society and Culture

Classification

Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.

Research

Attention Deficit Hyperactivity Disorder

Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all 6 non-controlled open-label studies in the review reported effectiveness, two small randomised controlled trials found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.

Substance Dependence

Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.

Other Uses

Aripiprazole is under development for the treatment of agitation and pervasive child development disorders. As of May 2021, it is in phase 3 clinical trials for these indications.

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An Overview of Outpatient Treatment for Mental Health?

Introduction

If an individual is struggling with their mental health there are various ways to help, however, if the individual is facing serious issues then it may be time to consider accessing professional treatment options.

Previously, ‘treatment’ may have elicited memories of facilities where locked doors, restricted movement, and visiting hours being restricted was the norm. While this type of treatment still exists (usually for the most seriously ill individuals and can be helpful in certain circumstances) there are also less restrictive therapeutic environments that can be helpful as well.

Outpatient mental health programmes, also known as structured outpatient, offer the same quality of treatment as inpatient mental health programmes, but generally with more freedom and flexibility – but what is the difference?

Inpatient versus Outpatient

Mental health treatment programmes generally fall into one of the below categories and, while equally focused on treatment, each type has unique attributes and benefits to offer.

ProgrammeOutline
Inpatient1. Also known as residential treatment programmes (and other names).
2. These are intensive, residential treatment programmes designed to treat serious mental health issues.
3. They require individuals to check themselves into a controlled environment to treat their mental health issues.
4. Individuals stay at a clinic/facility with 24-hour medical and emotional support.
5. May last days, weeks, or even months (in extreme cases years).
Day Care1. Also known as Intensive Day Care.
2. Can be used as a step-down from inpatient treatment or step-up from outpatient treatment.
3. Characterised by an individual attending a clinic/facility for a set number of full or half-days each week.
4. Particularly useful for individuals who do not need intensive 24-hour care for their mental health concerns, but still require some level of structured, ongoing support.
Outpatient1. Also known as non-residential treatment programmes (and other names).
2. These are part-time programmes designed to enable the individual to keep going to work or school during the day.
3. Less restrictive than inpatient programmes.
4. Usually require several hours per week visiting the clinic/facility.
5. Sessions can include mental health education (for the individual and family/friends) and individual/group counselling.
6. Can be a useful standalone option for individual’s with mild mental health issues, or part of a longer-term treatment programme.
7. May last several months or longer (e.g. more than one year).
Mixed1. Some clinics/facilities offer mixed treatment.
2. For example, a stay as an inpatient when a mental health crisis occurs, followed by outpatient treatment when this passes.

What is Outpatient Treatment for Mental Health?

Outpatient treatment refers to non-residential treatment, in which the individual spends structured time in treatment during the day or evening and returns home each night. Individuals who choose to participate in outpatient mental health treatment do so for a variety of reasons, including:

  • They may have small children at home or businesses to run and cannot take weeks or months out of their lives to live in a residential facility.
  • They may be transitioning out of an inpatient programme but still require the support and structure that outpatient treatment provides.

Outpatient treatment programmes are most beneficial for those with mild to moderate symptoms who have a strong support system at home.

Is It The Same As Outpatient Therapy?

Outpatient therapy is defined as “any psychotherapy service offered when the client is not admitted to a hospital, residential program, or other inpatient settings.”

  • Outpatient treatment usually provides:
    • A more comprehensive treatment experience.
    • More treatment hours.
  • Outpatient therapy can be part of outpatient treatment.

Who is Outpatient Treatment For?

Outpatient care is the most common treatment for many mental health problems due to:

  • Its lower cost;
  • Better flexibility to the individual’s needs and schedules; and
  • A larger selection of providers.

Outpatient care should only be applied when constant (professional) support is unnecessary and it is healthier for the individual to remain in their environment to experience stressors and learn to cope with professional guidance. This approach is often the best course of action for individuals with problems like eating disorders, depression, and anxiety.

For individual dealing with substance abuse, both inpatient and outpatient treatment plans are an option. The best choice depends on factors like mental health history, relapse history, and commitment to change. For any cases where the health or safety of the individual or those close to them is in question, inpatient care is likely necessary.

For many who undergo inpatient treatment, a long-term outpatient treatment plan is an important part of maintaining healthy habits and learning how to cope with daily life.

If an individual is at immediate risk of harming themselves or others, outpatient treatment is not the right level of care. Generally, individuals are a good fit for outpatient treatment if they are:

  • Motivated to participate in programming;
  • Able to learn and apply recovery skills;
  • Comfortable in a group setting;
  • Driven to improve their condition and work towards recovery; and
  • Willing to verbally express their thoughts and feelings.

Which Mental Health Conditions?

Outpatient treatment can be used to treat a wide variety of mental health concerns including:

  • Addictions (some providers state their addiction service is for adults only).
  • Attention deficit hyperactivity disorder (ADHD).
  • Alcohol use disorders.
  • Anxiety disorders.
  • Anorexia nervosa.
  • Autistic spectrum disorders (ASDs).
  • Bulimia nervosa.
  • Depressive disorders.
  • Dietetics.
  • Early identification of medically unexplained symptoms (MUS).
  • Obsessive compulsive disorder (OCD).
  • Post-traumatic stress disorder (PTSD).

This form of treatment can be beneficial for individuals who require ongoing therapeutic input for their mental health difficulties, but their challenges are not severe enough to require more intensive day care or inpatient treatment.

What Types of Outpatient Treatment are Available?

Outpatient treatment is not a one-size-fits-all programme and, therefore, should be tailored to the needs of the individual. However, programmes generally include some combination of:

  • Individual, group, and/or family/friend therapy.
  • Mental health education.
  • Managing symptoms.
  • Identifying triggers.
  • Overcoming fears.
  • Developing communication skills.
  • Establishing healthy social norms.
  • Coping skills/strategies.
  • Helping the individual to learn to thrive, rather than survive, outside the therapeutic environment.
  • Medication management.
  • Aftercare.
  • Counselling.
  • Psychoeducation.
  • Psychiatric care.
  • Personalised treatment/care plan.
  • Complementary therapies, for example: art therapy, yoga, and music therapy.

The exact combination will depend on the needs of the individual, and can change as the individual’s circumstances change.

With this in mind, an important element to consider is which type of outpatient treatment programme will be most beneficial to the individual. Broadly speaking, there are three main types of outpatient programmes, each with varying levels of structure, to consider. Further, while one individual may be able to manage their symptoms with an hour or two of mental health treatment per month, another individual may need more support and structure.

ProgrammeOutline
Standard Outpatient Treatment (SOT)1. This involves regular visits to the outpatient clinic, treatment centre, or hospital, as outlined by the individual’s personalised care plan.
2. Therapy sessions are scheduled around the individual’s work, school, and other responsibilities.
3. Treatment may be weekly or more frequent, and may continue for a year or more.
Intensive Outpatient Programme (IOP)1. At least six hours per week for adolescents and nine hour per week for adults, and this typically involves 3 to 4 hours of treatment for up to 5 days per week [1].
2. IOPs are designed to provide more structure and support than SOT while still allowing individuals the time and flexibility to tend to outside responsibilities.
3. The length of an IOP can be anywhere from a few weeks to a year – 90 days is usually the recommended minimum.
Partial Hospitalisation Programme (PHP)1. At least 20 hours per week, and this typically involves 6 or more hours of treatment per day, for up to 7 days per week [1].
2. Highly structured and supervised, PHPs provide the most intensive level of non-residential care, and are often beneficial for individuals reintegrating into their lives after an inpatient stay.
3. PHPs typically last around 30 days before the individual transitions to a more flexible level of care.

Notes

  1. The number of hours and days of treatment will vary between providers and clinics/facilities.

While traditional outpatient sessions may take place once a week and last around an hour, structured outpatient lasts anywhere from 6 to 35 hours per week. Individuals will often attend structured outpatient programmes three to five days per week.

Multidisciplinary Teams

Various professionals will make up a multidisciplinary team who will be involved in an individual’s outpatient treatment, and can include:

  • General practitioner (GP)/primary care physician.
  • District/mental health nurse.
  • Psychologist.
  • Psychiatrist.
  • Social worker.
  • Counsellor.

What are the Benefits of Outpatient Treatment?

For individuals with mild to moderate symptoms, (and preferably) strong support systems at home, and the ability to function independently, outpatient treatment is usually a good choice. With this in mind, individuals can benefit because they can:

  • Receive an intense level of programming (much like inpatient treatment) without entirely disrupting their current situation in life, such as work, school or family responsibilities;
  • Turn to outpatient treatment after completing an inpatient programme as part of their continued recovery journey;
  • Return home each night (the home environment can be beneficial for recovery provided that it is a healthy, stable environment);
  • Stay connected with family and friends ones while still receiving the treatment they need;
  • Maintain commitments and responsibilities, such as work and school;
  • Receive extra support from healthcare professionals and fellow participants;
  • Spend more time at the treatment centre, which enables them to focus their attention on recovery;
  • Apply the skills and strategies they learn in treatment to real life situations;
  • Stay connected with their treatment team and remain accountable to their personalised care plan; and
  • Transition slowly back into everyday situations, equipped with tools to help optimise their independence and live a meaningful life.

Outpatient treatment can also be conducted via telehealth, so individuals (for example) living in rural areas or with transport issues do not (always) have to travel to receive services (although telehealth provision varies between countries and providers).

Depending on the country the individual resides in, most outpatient treatment programmes also have the added benefit of being less expensive than inpatient programmes. The on-hand medical care and psychotherapy available as an inpatient increases treatment costs, however, the price difference should not encourage or discourage an individual from choosing the most appropriate treatment for them.

Summary

Mental health treatment can be thought of as a continuum, with individuals moving up or down in levels of care as needed. However, it is important that both the individual (with a mental health issue) and their family/friends understand the differences before selecting a treatment programme. Exploring all options prior to making a decision can put you or a loved one on their journey to better long-term mental health.

No matter which treatment option an individual may choose, mental health treatment programmes can help change their life for the better. Mental health issues can be chronic and recovery a lifelong process.

What is Climazolam?

Introduction

Climazolam was introduced under licence as a veterinary medicine by the Swiss Pharmaceutical company Gräub under the tradename Climasol.

Background

Climazolam is a benzodiazepine, specifically an imidazobenzodiazepine derivative developed by Hoffman-LaRoche.

It is similar in structure to midazolam and diclazepam and is used in veterinary medicine for anaesthetising animals.

What is Midazolam?

Introduction

Midazolam, sold under the brand name Versed, among others, is a benzodiazepine medication used for anaesthesia, procedural sedation, trouble sleeping, and severe agitation.

It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. It is important to note that this drug does not cause an individual to become unconscious, merely be sedated. It is also useful for the treatment of seizures. Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last between one and six hours.

Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.

Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organisation’s List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.

Brief History

Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anaesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a “truth serum” on terrorist suspects in project “Medication”.

Medical Uses

Seizures

Midazolam is sometimes used for the acute management of seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus that has not improved following other treatments or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.

Drawbacks include a high degree of breakthrough seizures – due to the short half-life of midazolam – in over 50% of people treated, as well as treatment failure in 14-18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. There is evidence buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

Procedural Sedation

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for preoperative sedation, for the induction of general anaesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.

Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.

Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.

Agitation

Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.

End of Life Care

In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, myoclonus, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.

Administration

Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular.

  • Dosing:
    • Perioperative use: 0.15 to 0.40 mg/kg IV.
    • Premedication: 0.07 to 0.10 mg/kg IM.
    • Intravenous sedation: 0.05 to 0.15 mg/kg IV.

Contraindications

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side Effects

Refer to Long-Term Effects of Benzodiazepines.

Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.

Long-term use of benzodiazepines has been associated with long-lasting deficits of memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behaviour or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After night-time administration of midazolam, residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A “midazolam infusion syndrome” may result from high doses, and is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.

In susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behaviour, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behaviour is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.

Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnoea becomes more likely.

Although the incidence of respiratory depression/arrest is low (0.1-0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug.

Pregnancy and Breastfeeding

Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhoea or vomiting). Breastfeeding by mothers using midazolam is not recommended.

Elderly

Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

Tolerance, Dependence, and Withdrawal

A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a person’s underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhoea, tachycardia, hypertension, and tachypnoea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus that may be fatal.

Overdose

Refer to Benzodiazepine Overdose.

A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and risk of death is also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.

Symptoms of midazolam overdose can include:

  • Ataxia.
  • Dysarthria.
  • Nystagmus.
  • Slurred speech.
  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Hypotension.
  • Respiratory arrest.
  • Vasomotor collapse.
  • Impaired motor functions:
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
  • Coma.
  • Death.

Detection in Body Fluids

Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalised patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.

Interactions

Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John’s wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolised almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St John’s wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

Pharmacology

Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5-2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl- channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.

Pharmacokinetics

  • Volume of Distribution: 1-2.5L/kg in normal healthy individuals.
  • Protein Binding: 96% Plasma protein bound.
  • Onset of Action: 3-15 minutes.
  • Elimination Half-Life: 1.5-3 hours.

Society and Culture

Cost

Midazolam is available as a generic medication.

Availability

Midazolam is available in the United States as a syrup or as an injectable solution.

Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with “Roche” on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavour. It becomes soluble when the injectable solution is buffered to a pH of 2.9-3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.

Legal Status

In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.

Marketing Authorisation

In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the trade name Buccolam. Buccolam was approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.

Use in Executions

The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter’s manufacturer disallowed that drug’s use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner’s breathing and heart, respectively. Due to the fact that the condemned prisoner is not unconscious but merely sedated, two very different things, those following two drugs can cause extreme pain and panic in the soon to die prisoner.

Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.

The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett’s vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or to a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled.

Notable Incidents

The state of Florida used midazolam to execute William Frederick Happ in October 2013.

The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.

The execution of Ronald Bert Smith in the state of Alabama on 08 December 2016, “went awry soon after (midazolam) was administered” again putting the effectiveness of the drug in question.

In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, and potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte’s lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.

On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.

On 28 October 2021, the state of Oklahoma carried out the execution of inmate John Marion Grant, 60, using midazolam as part of its three-drug cocktail hours after the US Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the state’s first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09 pm, Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15 pm., officials said Grant was unconscious, and he was pronounced dead at 4:21 pm.

Legal Challenges

In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the US Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.

The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under false pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.

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What is Amisulpride?

Introduction

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes.

It is sold under the brand names Barhemsys (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic). It is also used to treat dysthymia.

It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.

Amisulpride is indicated for use in the US in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

Amisulpride is believed to work by blocking, or antagonising, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorised to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.

It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available. It is marketed in all English-speaking countries except for Canada. A New York City based company, LB Pharmaceuticals, has announced the ongoing development of LB-102, also known as N-methyl amisulpride, an antipsychotic specifically targeting the United States. A poster presentation at European Neuropsychopharmacology seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.

Brief History

The US Food and Drug Administration (FDA) approved amisulpride based on evidence from four clinical trials of 2323 subjects undergoing surgery or experiencing nausea and vomiting after the surgery. The trials were conducted at 80 sites in the United States, Canada and Europe.

Two trials (Trials 1 and 2) enrolled subjects scheduled to have surgery. Subjects were randomly assigned to receive either amisulpride or a placebo drug at the beginning of general anaesthesia. In Trial 1, subjects received amisulpride or placebo alone, and in Trial 2, they received amisulpride or placebo in combination with one medication approved for prevention of nausea and vomiting. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the surgery. The results then compared amisulpride to placebo.

The other two trials (Trials 3 and 4) enrolled subjects who were experiencing nausea and vomiting after surgery. In Trial 3, subjects did not receive any medication to prevent nausea and vomiting before surgery and in Trial 4 they received the medication, but the treatment did not work. In both trials, subjects were randomly assigned to receive either amisulpride or placebo. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the treatment. The trial compared amisulpride to placebo.

Medical Uses

Schizophrenia

Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia. Amisulpride augmentation, similarly to sulpiride augmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia. Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.

Postoperative Nausea and Vomiting

Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

Contraindications

Amisulpride’s use is contraindicated in the following disease states:

  • Pheochromocytoma.
  • Concomitant prolactin-dependent tumours e.g. prolactinoma, breast cancer.
  • Movement disorders (e.g. Parkinson’s disease and dementia with Lewy bodies).
  • Lactation.
  • Children before the onset of puberty.

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.

Adverse Effects

  • Very Common (≥10% incidence):
    • Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism).
  • Common (≥1%, <10% incidence):
    • Insomnia.
    • Hypersalivation.
    • Nausea.
    • Headache.
    • Hyperactivity.
    • Vomiting.
    • Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.).
    • Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine).
    • Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
      • Constipation.
      • Dry mouth.
      • Disorder of accommodation.
      • Blurred vision.
  • Rare (<1% incidence):
    • Hyponatraemia.
    • Bradycardia.
    • Hypotension.
    • Palpitations.
    • Urticaria.
    • Seizures.
    • Mania.
    • Oculogyric crisis.
    • Tardive dyskinesia.
    • Blood dyscrasias such as leucopenia, neutropenia and agranulocytosis.
    • QT interval prolongation (in a recent meta-analysis of the safety and efficacy of 15 antipsychotic drugs amisulpride was found to have the 2nd highest effect size for causing QT interval prolongation).
    • Somnolence.

Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2 receptors including those in the anterior pituitary.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose

Torsades de pointes is common in overdose. Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).

Interactions

Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.), reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.

Pharmacology

Pharmacodynamics

Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.

Amisulpride and its relatives sulpiride, levosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).

Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).

Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM). Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterise the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice. The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride. These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.

Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist. The clinical implications of this, if any, are unclear. In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.

Amisulpride shows stereoselectivity in its actions. Aramisulpride ((R)-amisulpride) has higher affinity for the 5-HT7 receptor (Ki = 47 nM vs. 1,900 nM) while esamisulpride ((S)-amisulpride) has higher affinity for the D2 receptor (4.0 nM vs. 140 nM). An 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) which provides more balanced 5-HT7 and D2 receptor antagonism than racemic amisulpride (50:50 ratio of enantiomers) is under development for the treatment of bipolar depression.

Society and Culture

Brand Names

Brand names include: Amazeo, Amipride (AU), Amival, Solian (AU, IE, RU, UK, ZA), Soltus, Sulpitac (IN), Sulprix (AU), Midora (RO) and Socian (BR).

Availability

Amisulpride was not approved by the Food and Drug Administration for use in the United States until February 2020, but it is used in Europe, Israel, Mexico, India, New Zealand and Australia to treat psychosis and schizophrenia.

An IV formulation of Amisulpride was approved for the treatment of postoperative nausea and vomiting (“PONV”) in the United States in February 2020.

This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Amisulpride&gt;; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Amineptine?

Introduction

Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family.

It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser extent as a norepinephrine reuptake inhibitor.

Amineptine was developed by the French Society of Medical research in the 1960s. Introduced in France in 1978 by the pharmaceutical company Servier, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant effect experienced by some patients.

After its release into the European market, cases of hepatotoxicity emerged, some serious. This, along with the potential for abuse, led to the suspension of the French marketing authorization for Survector in 1999.

Amineptine was never approved by the US Food and Drug Administration (FDA) for marketing in the US, meaning that it is not legal to market or sell amineptine for any medical uses in the US.

Medical Uses

Amineptine was approved in France for severe clinical depression of endogenous origin in 1978.

Contraindications

  • Chorea
  • Hypersensitivity: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product.
  • MAO inhibitors.

Precautions for Use

Warnings and precautions before taking amineptine:

  • Breast feeding.
  • Children less than 15-year of age.
  • General anaesthesia: Discontinue the drug 24 to 48 hours before anaesthesia.
  • Official sports/Olympic Games: Prohibited substance.
  • Pregnancy (first trimester).

Effects on the Foetus

  • Lacking information in humans.
  • Non-teratogenic in rodents.

Side Effects

Dermatological

Severe acne due to amineptine was first reported in 1988 by various authors – Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few – simultaneously in the same issue of Annales de dermatologie et de vénéréologie and in the 12 March 1988 issue of The Lancet. A year later, Dr Martin-Ortega and colleagues in Barcelona, Spain reported a case of “acneiform eruption” in a 54-year-old woman whose intake of amineptine was described as “excessive.” One year after that, Vexiau and colleagues reported six women, one of whom never admitted to using amineptine, getting severe acne concentrated in the face, back and thorax, the severity of which varied with the dosage. Most of them were treated unsuccessfully with isotretinoin (Accutane) for about 18 months; two of the three that discontinued amineptine experienced a reduction in cutaneous symptoms, with the least affected patient going into remission.

Psychiatric

Psychomotor excitation can very rarely occur with this drug.

  • Insomnia.
  • Irritability.
  • Nervousness.
  • Suicidal ideation. Seen early in the treatment, by lifting of psychomotor inhibition.

Abuse and Dependence

The risk of addiction is low, but exists nonetheless. Between 1978 and 1988, there were 186 cases of amineptine addiction reported to the French Regional Centres of Pharmacovigilance; an analysis of 155 of those cases found that they were predominantly female, and that two-thirds of cases had known risk factors for addiction. However, a 1981 study of known opiate addicts and schizophrenia patients found no drug addiction in any of the subjects. In a 1990 study of eight amineptine dependence cases, the gradual withdrawal of amineptine could be achieved without problems in six people; in two others, anxiety, psychomotor agitation, and/or bulimia appeared.

Withdrawal

Pharmacodependence is very common with amineptine compared to other antidepressants. A variety of psychological symptoms can occur during withdrawal from amineptine, such as anxiety and agitation.

Cardiovascular

Very rarely:

  • Arterial hypotension.
  • Palpitations.
  • Vasomotor episode.

Hepatic

Amineptine can rarely cause hepatitis, of the cytolytic, cholestatic varieties. Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an immunoallergic reaction. It resolves upon discontinuation of the offending drug. The risk of getting this may or may not be genetically determined.

Additionally, amineptine is known to rarely elevate transaminases, alkaline phosphatase, and bilirubin.

Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. Often preceded by sometimes intense abdominal pains, nausea, vomiting or a rash, the jaundice is variable. Hepatitis is either of mixed type or with cholestatic prevalence. The evolution was, in all the cases, favourable to the discontinuation of the drug. The mechanism is discussed (immunoallergic and/or toxic).

In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.

Lazaros and colleagues at the Western Attica General Hospital in Athens, Greece reported two cases of drug induced hepatitis 18 and 15 days of treatment.

One case of cytolytic hepatitis occurred after ingestion of only one tablet.

Gastrointestinal

Acute pancreatitis (very rare) A case associating acute pancreatitis and mixed hepatitis after three weeks of treatment.

Immunological

In 1989, Sgro and colleagues at the Centre de Pharmacovigilance in Dijon reported a case of anaphylactic shock in a woman who had been taking amineptine.

Pharmacology

Pharmacodynamics

Amineptine inhibits the reuptake of dopamine and, to a much lesser extent, of norepinephrine. In addition, it has been found to induce the release of dopamine. However, amineptine is much less efficacious as a dopamine releasing agent relative to D-amphetamine, and the drug appears to act predominantly as a dopamine reuptake inhibitor. In contrast to the case for dopamine, amineptine does not induce the release of norepinephrine, and hence acts purely as a norepinephrine reuptake inhibitor. Unlike other TCAs, amineptine interacts very weakly or not at all with the serotonin, adrenergic, dopamine, histamine, and muscarinic acetylcholine receptors. The major metabolites of amineptine have similar activity to that of the parent compound, albeit with lower potency.

No human data appear to be available for binding or inhibition of the monoamine transporters by amineptine.

Pharmacokinetics

Peak plasma levels of amineptine following a single 100 mg oral dose have been found to range between 277 and 2,215 ng/mL (818-6,544 nM), with a mean of 772 ng/mL (2,281 nM), whereas maximal plasma concentrations of its major metabolite ranged between 144 and 1,068 ng/mL (465–3,452 nM), with a mean of 471 ng/mL (1,522 nM). After a single 200 mg oral dose of amineptine, mean peak plasma levels of amineptine were around 750 to 940 ng/mL (2,216-2,777 nM), while those of its major metabolite were about 750 to 970 ng/mL (2,216-3,135 nM). The time to peak concentrations is about 1 hour for amineptine and 1.5 hours for its major metabolite. The elimination half-life of amineptine is about 0.80 to 1.0 hours and that of its major metabolite is about 1.5 to 2.5 hours. Due to their very short elimination half-lives, amineptine and its major metabolite do not accumulate significantly with repeated administration.

Society and Culture

Brand Names

Amineptine has been sold under a variety of brand names including Survector, Maneon, Directim, Neolior, Provector, and Viaspera.

Legal Status

It had been proposed that Amineptine become a Schedule I controlled substance in the United States in July 2021.

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What is Benzatropine?

Introduction

Benzatropine (an international non-proprietary name, INN), known as benztropine in the United States and Japan, is a medication used to treat a type of movement disorder due to antipsychotics known as dystonia and parkinsonism.

It is not useful for tardive dyskinesia. It is taken by mouth or by injection into a vein or muscle. Benefits are seen within two hours and last for up to ten hours.

Common side effects include dry mouth, blurry vision, nausea, and constipation. Serious side effect may include urinary retention, hallucinations, hyperthermia, and poor coordination. It is unclear if use during pregnancy or breastfeeding is safe. Benzatropine is an anticholinergic which works by blocking the activity of the muscarinic acetylcholine receptor.

Benzatropine was approved for medical use in the United States in 1954. It is available as a generic medication. In 2017, it was the 226th most commonly prescribed medication in the United States, with more than two million prescriptions. It is sold under the brand name Cogentin among others.

Medical Uses

Benzatropine is used to reduce extrapyramidal side effects of antipsychotic treatment. Benzatropine is also a second-line drug for the treatment of Parkinson’s disease. It improves tremor, and may alleviate rigidity and bradykinesia. Benzatropine is also sometimes used for the treatment of dystonia, a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.

Adverse Effects

These are principally anticholinergic:

  • Dry mouth.
  • Blurred vision.
  • Cognitive changes.
  • Drowsiness.
  • Constipation.
  • Urinary retention.
  • Tachycardia.
  • Anorexia.
  • Severe delirium and hallucinations (in overdose).

While some studies suggest that use of anticholinergics increases the risk of tardive dyskinesia (a long-term side effect of antipsychotics), other studies have found no association between anticholinergic exposure and risk of developing tardive dyskinesia, although symptoms may be worsened.

Drugs that decrease cholinergic transmission may impair storage of new information into long-term memory. Anticholinergic agents can also impair time perception.

Pharmacology

Benzatropine is a centrally acting anticholinergic/antihistamine agent. It is a selective M1 muscarinic acetylcholine receptor antagonist. Benzatropine partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity. Animal studies have indicated that anticholinergic activity of benzatropine is approximately one-half that of atropine, while its antihistamine activity approaches that of mepyramine. Its anticholinergic effects have been established as therapeutically significant in the management of Parkinsonism. Benzatropine antagonises the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early Parkinson’s disease.

Benzatropine analogues are atypical dopamine reuptake inhibitors, which might make them useful for people with akathisia secondary to antipsychotic therapy.

Benzatropine also acts as a functional inhibitor of acid sphingomyelinase (FIASMA).

Benzatropine has been also identified, by a high throughput screening approach, as a potent differentiating agent for oligodendrocytes, possibly working through M1 and M3 muscarinic receptors. In preclinical models for multiple sclerosis, benzatropine decreased clinical symptoms and enhanced re-myelination.

Other Animals

In veterinary medicine, benzatropine is used to treat priapism in stallions.

Naming

Since 1959, benzatropine is the official INN name of the medication under the INN scheme, the medication naming system coordinated by the World Health Organisation (WHO); it is also the British Approved Name (BAN) given in the British Pharmacopoeia, and has been the official non-proprietary name in Australia since 2015. Regional variations of the “a” spelling are also used in French, Italian, Portuguese, and Spanish, as well as Latin (all medications are assigned a Latin name by WHO).

“Benztropine” is the official United States Adopted Name (USAN), the medication naming system coordinated by the USAN Council, co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA). It is also the Japanese Accepted Name (JAN) and was used in Australia until 2015, when it was harmonised with the INN.

Both names may be modified to account for the methanesulfonate salt as which the medication is formulated: the modified INN (INNm) and BAN (BANM) is benzatropine mesilate, while the modified USAN is benztropine mesylate. The modified JAN is a hybrid form, benztropine mesilate.

The misspelling benzotropine is also occasionally seen in the literature.